From the middle of the 1950's valve replacement operations have been practiced. A wide variety of artificial valves have been developed and widely used for replacement of aortic valves, mitral valves, tricuspid valves, etc. and in artificial hearts.
Artificial valves are classified broadly into mechanoprosthetic valves and bioprosthetic valves. Mechanoprosthetic valves are further classified roughly into ball-type valves and disc-type valves, depending on the shape of moving portions. However, both types of the mechanoprosthetic valves have the following disadvantages: (1) there is not parallel flow through the bloodstream used therewith, (2) the materials which are used to make the valves readily form thrombus and deteriorate blood components to cause hemolysis, and (3) the sounds made by the valves have an adverse psychological effect on the patient.
Bioprosthetic valves which are now clinically used include porcine aortic valves treated with glutaraldehyde (hereinafter referred to as "GA") and bovine pericardia formed into the shape of a valve cusp. Such valves have an excellent antithrombogenic property. This eliminates the need to use long term warfarin anticoagulants which can possibly cause cerebral hemorrhaging. Such valves also have hemodynamic properties which provide a central blood flow characteristic. However, these valves have problems in durability in that the physical properties of the valve are such that calcium deposits on valve cusp tissues, and cracks and perforation are caused by fatiguing of valves.
Valves using biological tissues are cross-linked with GA, in order to maintain their strengths, to suppress their being absorbed into living bodies, and to reduce their antigenic property. However, the cross-linking with GA treatment inevitably makes the biological tissues stiff. The stiffened valve cusps behave differently from untreated, natural valves. Abnormal behaviors of the stiffened valve cusps become more remarkable at lower blood pressures.
About half of GA treated valves can become dysfunctional 5 to 10 years after their implantation into human bodies due to calcification and cracking. In young children showing a vigorous calcium metabolism, almost all the GA treated valves implanted are subject to calcification and become dysfunctional even earlier after the implantation, namely, after 2-6 years.
Thus, GA has various disadvantages as a cross-linking agent a biological tissue to be used as a valve in the body of humans and mammals.
The following requirements of a cross-linking agent for cross-linking biological tissue will provide an ideal bioprosthetic valve:
(1) excludes completely the antigenicity of heterologous animal tissues; PA1 (2) prevents the invasion of calcium into biological tissues; PA1 (3) has persistent sterilizing effects and strong resistance to infections; PA1 (4) is free from deterioration of flexibility and elasticity of biological tissues and allows valves to behave in a manner similar to natural valves; and PA1 (5) provides valves with excellent tensile strength and torsional strength.
Ideal cross-linking agents which can be substituted for GA and satisfy the above-noted requirements have long been desired.